Mechanisms of the protective effects of urocortin on coronary endothelial function during ischemia-reperfusion in rat isolated hearts

Activation of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome cascade has a role in the pathogenesis of ischemia/reperfusion (IR) injury. There is growing evidence indicating cytochrome p450 (CYP450)-derived metabolites of n-3 and n-6 polyunsaturated fatty acids (PUFAs) possess both adverse and protective effects in the heart. CYP-derived epoxy metabolites are rapidly hydrolyzed by the soluble epoxide hydrolase (sEH). The current study hypothesized that the cardioprotective effects of inhibiting sEH involves limiting activation of the NLRP3 inflammasome. Isolated hearts from young wild-type (WT) and sEH null mice were perfused in the Langendorff mode with either vehicle or the specific sEH inhibitor t-AUCB. Improved post-ischemic functional recovery and better mitochondrial respiration were observed in both sEH null hearts or WT hearts perfused with t-AUCB. Inhibition of sEH markedly attenuated the activation of the NLRP3 inflammasome complex and limited the mitochondrial localization of the fission protein dynamin-related protein-1 (Drp-1) triggered by IR injury. Cardioprotective effects stemming from the inhibition of sEH included preserved activities of both cytosolic thioredoxin (Trx)-1 and mitochondrial Trx-2 antioxidant enzymes. Together, these data demonstrate that inhibiting sEH imparts cardioprotection against IR injury via maintaining post-ischemic mitochondrial function and attenuating a detrimental innate inflammatory response.

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PROTECTIVE EFFECTS OF AN INDENOINDOLE ANTIOXIDANT ON CORONARY ENDOTHELIAL FUNCTION AFTER LONG-TERM STORAGE

Transplantation Journal ◽

10.1097/00007890-199510000-00002 ◽

1995 ◽

Vol 60 (8) ◽

pp. 774-777 ◽

Cited By ~ 6

Author(s):

LARS WIKLUND ◽

VIRGINIA M. MILLER ◽

CHRISTOPHER G. A. MCGREGOR ◽

PER-OVE SJÖQUIST ◽

HÅÅKAN BERGGREN ◽

...

Keyword(s):

Endothelial Function ◽

Protective Effects ◽

Coronary Endothelial Function ◽

Long Term Storage ◽

Term Storage

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Urocortin Protects Coronary Endothelial Function During Ischemia-Reperfusion: A Brief Communication

Experimental Biology and Medicine ◽

10.1177/153537020422900114 ◽

2004 ◽

Vol 229 (1) ◽

pp. 118-120 ◽

Cited By ~ 11

Author(s):

Angel Luis García-Villalón ◽

Elena Sanz ◽

Luis Monge ◽

Nuria Fernández ◽

Belén Climent ◽

...

Keyword(s):

Endothelial Function ◽

Ischemia Reperfusion ◽

Coronary Endothelial Function

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PROTECTIVE EFFECTS OF AN INDENOINDOLE ANTIOXIDANT ON CORONARY ENDOTHELIAL FUNCTION AFTER LONG-TERM STORAGE

Transplantation Journal ◽

10.1097/00007890-199510270-00002 ◽

1995 ◽

Vol 60 (8) ◽

pp. 774-777

Author(s):

LARS WIKLUND ◽

VIRGINIA M. MILLER ◽

CHRISTOPHER G. A. MCGREGOR ◽

PER-OVE SJÖQUIST ◽

HÅÅKAN BERGGREN ◽

...

Keyword(s):

Endothelial Function ◽

Protective Effects ◽

Coronary Endothelial Function ◽

Long Term Storage ◽

Term Storage

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Coenzyme Q10 protects coronary endothelial function from ischemia reperfusion injury via an antioxidant effect

Surgery ◽

10.1016/s0039-6060(96)80287-x ◽

1996 ◽

Vol 120 (2) ◽

pp. 189-196 ◽

Cited By ~ 35

Author(s):

Hitoshi Yokoyama ◽

David M. Lingle ◽

Juan A. Crestanello ◽

Joseph Kamelgard ◽

Brian R. Kott ◽

...

Keyword(s):

Endothelial Function ◽

Reperfusion Injury ◽

Coenzyme Q10 ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Antioxidant Effect ◽

Coronary Endothelial Function

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Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00400.2015 ◽

2016 ◽

Vol 310 (11) ◽

pp. E947-E957 ◽

Cited By ~ 41

Author(s):

Rui Wei ◽

Shifeng Ma ◽

Chen Wang ◽

Jing Ke ◽

Jin Yang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Endothelial Cells ◽

Endothelial Function ◽

No Production ◽

Dependent Manner ◽

Protective Effects ◽

Newly Diagnosed ◽

Coronary Endothelial Function ◽

Enos Phosphorylation

Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9–39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9–39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.

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Protection of Coronary Endothelial Function during Cardiac Surgery: Potential of Targeting Endothelial Ion Channels in Cardioprotection

BioMed Research International ◽

10.1155/2014/324364 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Qin Yang ◽

Cheuk-Man Yu ◽

Guo-Wei He ◽

Malcolm John Underwood

Keyword(s):

Endothelial Cells ◽

Blood Flow ◽

Cardiac Surgery ◽

Ion Channels ◽

Endothelial Function ◽

Trp Channels ◽

Ischemia Reperfusion ◽

Critical Role ◽

Coronary Endothelial Function ◽

Vasoactive Factors

Vascular endothelium plays a critical role in the control of blood flow by producing vasoactive factors to regulate vascular tone. Ion channels, in particular, K+channels and Ca2+-permeable channels in endothelial cells, are essential to the production and function of endothelium-derived vasoactive factors. Impairment of coronary endothelial function occurs in open heart surgery that may result in reduction of coronary blood flow and thus in an inadequate myocardial perfusion. Hyperkalemic exposure and concurrent ischemia-reperfusion during cardioplegic intervention compromise NO and EDHF-mediated function and the impairment involves alterations of K+channels, that is,KATPandKCa, and Ca2+-permeable TRP channels in endothelial cells. Pharmacological modulation of these channels during ischemia-reperfusion and hyperkalemic exposure show promising results on the preservation of NO and EDHF-mediated endothelial function, which suggests the potential of targeting endothelial K+and TRP channels for myocardial protection during cardiac surgery.

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One-day Hypothermic Preservation of Isolated Hearts with Halothane Improves Cardiac Function Better than Low Calcium

Anesthesiology ◽

10.1097/00000542-199511000-00020 ◽

1995 ◽

Vol 83 (5) ◽

pp. 1065-1077 ◽

Cited By ~ 9

Author(s):

David F. Stowe ◽

Helmut Habazettl ◽

Bernhard M. Graf ◽

John P. Kampine ◽

Zeljko J. Bosnjak

Keyword(s):

Ischemia Reperfusion Injury ◽

Isolated Heart ◽

Ischemia Reperfusion ◽

Negative Inotropic Effect ◽

Protective Effects ◽

Isolated Hearts ◽

Hypothermic Preservation ◽

Normothermic Perfusion ◽

Heart Study ◽

Better Than

Abstract Background Halothane exerts a potent negative inotropic effect on the heart and mimics many of the cardiac effects of lowered extracellular CaCl2. Reduced slow inward Calcium2+ current and sarcoplasmic reticular effects on intracellular Calcium2+ are likely involved. The authors reported previously that halothane protects against hypoxic and ischemia reperfusion injury in isolated hearts. The aim of this isolated heart study was to compare protective effects of halothane and low CaCl sub 2 (0.5 mM) administered during 1 day of hypothermic perfusion on return of normothermic perfusion.

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